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End point

SECONDARY

The primary endpoints included changes in MBG, SDBG, MAGE, PPGE, LAGE, MODD, TIR, breakfast AUCpp, lunch AUCpp, and dinner AUCpp readings during the screening period, lead-in period, and after 12 weeks of treatment.The secondary endpoints were changes in HbA1c, FBG, 1h-PBG, 2h-PBG, fasting blood lipids, postprandial blood lipids at baseline and after 12 weeks of treatment.

PMC10653384

Statistical method

All statistical analyses were performed using SPSS 25.0. For normally-distributed numerical variables, one-way analysis of variance (ANOVA) was used to compare differences between groups, and paired Student’s t-tests were used before and after treatment to assess differences in intra-group outcome measures. For non-normally distributed variables, the Kruskal–Wallis test was used to compare intergroup differences, and the Wilcoxon signed-rank test was used to assess differences in intra-group outcome measures before and after the interventions. The Bonferroni method was used for

PMC10653384

Results

PMC10653384

Baseline patient characteristics

T2DM, TG, diabetes

INS, DIABETES

We included 30 patients with T2DM for whom blood glucose levels could not be successfully controlled. Of them, 10 were assigned to each of the INS, INS+Met, and INS+SZ-A groups. No significant differences were observed in the general characteristics (such as age, sex ratio, weight, BMI, waist circumference, waist-to-hip ratio, and duration of diabetes) and efficacy and safety indicators (including CHOL, TG, HDL,LDL, FBG, HbA1c, HOMA-IR (CP), ALT, AST, Cr, UA, OGTT AUC (h·mmol/L), and insulin dose)between the three groups (P >0.05; Baseline data of three groups.All P>0.05, Fisher’s precision probability test, one-way ANOVA, Kruskal-Wallis H test or Fisher’s precision probability test were performed among the three groups.

PMC10653384

General conditions at baseline and after the 12-week treatment

TG

Compared those during screening period, HbA1c and FBG in the three groups were significantly improved after 12 weeks of treatment (P<0.05), but weight changes were not statistically significant (P>0.05). Compared with those during the lead-in period, the insulin doses in the Ins+Met and Ins+SZ-A groups decreased after 12 weeks of treatment (P<0.05). After 12-week treatment, the HbA1c, FBG and insulin dosages of Ins+Met and Ins+SZ-A groups were lower than those of the Ins group (P<0.05), and there was no statistically significant difference in weight between the three groups (P>0.05; General conditions at baseline and after 12-week treatment.*represents P < 0.05 (comparison between baseline and after 12-week treatment in each group). Compared with those in the screening period, the TG and HDL indicators of the Ins+Met group (P<0.05), the TG, HDL and LDL levels of the Ins+SZ-A group (P<0.05), and the LDL levels of the Ins group (P<0.05) all improved after the 12 weeks of treatment, there were no significant differences in the other indicators (P<0.05). After 12 weeks treatment, the improvement in TG and HDL levels seen in the Ins+Met and Ins+SZ-A groups was greater than those in the Ins group (P<0.05). There were no significant differences in the other indicators (P>0.05;

PMC10653384

Fasting and postprandial blood glucose and lipid levels after 12 weeks of treatment

TG

BLOOD

After 12 weeks of treatment, FBG and 1h-PBG levels were lower in the Ins+Met and Ins+SZ-A groups than in the Ins group (P<0.05;Fasting and Postprandial Blood Glucose and Lipid Levels After 12 Weeks of Treatment After 12 weeks of treatment, the fasting TG, 1-hour postprandial TG, 2-hour postprandial TG, and TG AUC indicators were lower in the Ins+Met and Ins+SZ-A groups than in the Ins group (P<0.05;

PMC10653384

Continuous glucose monitoring results

No statistically significant differences were noted in terms of CGM indicators such as MBG, SDBG, LAGE, PPGE, MAGE, MODD, TIR, breakfast AUCpp, lunch AUCpp, and dinner AUCpp among the three groups during the screening and lead-in period (P>0.05). Compared to the screening period, the MBG, SDBG, LAGE, PPGE, MAGE, MODD, TIR, breakfast AUCpp, lunch AUCpp, and dinner AUCpp indicators of all three groups showed significant improvements during the lead-in period (P<0.05; CGM results.*represents P < 0.05(comparison between screening and lead-in period for each group,matched-samples Student’s t- test).#represents P < 0.05(comparison between lead-in and after 12-week treatment period for each group,matched-samples Student’s t- test).CGM results Changes in MBG Compared with those during the lead-in period, the Ins+Met and Ins+SZ-A groups showed significant improvements in terms of MBG, SDBG, LAGE, PPGE, MAGE, TIR, breakfast AUCpp, lunch AUCpp, and dinner AUCpp after the 12-week treatments (P<0.05); there was no statistically significant difference observed in MODD (P>0.05). None of these indicators improved significantly in the Ins group (P>0.05). After 12 weeks of treatment,the MBG, SDBG, TIR,breakfast AUCpp, and lunch AUCpp indicators of the Ins+Met and Ins+SZ-A groups showed significantly greater than those of the Ins group (P<0.05).In addition, the LAGE, PPGE, MAGE, and dinner AUCpp levels of the Ins+SZ-A group were lower than those of the Ins+Met nd Ins groups (P<0.05). However,there were no statistically significant differences in MODD among the three groups (P>0.05;

PMC10653384

Adverse reactions

diarrhea, hypoglycemic reactions

ADVERSE REACTIONS, EVENTS, HYPOGLYCEMIC REACTIONS

After 12 weeks of treatment, there were no statistically significant changes in ALT, AST, Cr, and UA in any of the groups (P>0.05). The three treatment regimens did not show any severe hypoglycemic reactions during any of the study phases. There were no significant differences in the hypoglycemic responses of the three groups during the screening, lead-in, and after 12-week treatments periods (P>0.05). One case of abdominal distension and one case of diarrhea occurred in the Ins+Met group, and the Ins+SZ-A group experienced one case of abdominal distension and no cases of diarrhea. The patients who experienced these events received appropriate medications administered during mealtimes, starting with low doses that were then gradually increased until the adverse reactions were ameliorated, without altering their main treatment regimens.

PMC10653384

Discussion

flatulence, diarrhea, abdominal pain, TIR, hypoglycemia, hyperglycemia, reduced fasting blood lipids, ’ blood glucose, abdominal distension, postprandial hyperglycemia, T2DM, diabetes

HYPERLIPIDEMIA, ASYMPTOMATIC HYPOGLYCEMIA, HYPOGLYCEMIA, HYPERGLYCEMIA, DIABETIC COMPLICATIONS, DIABETES

It is important to reach the target levels for blood glucose and HbA1c when treating patients with T2DM. Good control over blood glucose fluctuations is also important. Patients with diabetes who have similar HbA1c levels may have different blood glucose stabilities, and large blood glucose fluctuations may be associated with a greater risk of diabetic complications (In this study, the three treatment regimens all improved the patients’ blood glucose levels, and the results in the Ins+SZ-A group were superior to those in the Ins+Met and Ins groups in terms of improving postprandial blood glucose fluctuations. All three treatment regimens reduced fasting blood lipids, but the Ins+Met and Ins+SZ-A treatments also improved the patients’ postprandial blood lipid indicators.HbA1c, which reflects long-term blood glucose control, has become the gold standard for evaluating blood glucose control and guiding clinical decisions regarding the management of diabetes. Compared to during the screening period, the HbA1c and FBG levels in all three groups decreased following the 12-week treatment period. After 12 weeks treatment, the HbA1c, FBG, and administered insulin doses in the Ins+Met and Ins+SZ-A groups were lower than those in the Ins group. The insulin doses in the Ins+Met and Ins+SZ-A groups during the lead-in period were 29.00 (24.00, 34.5) and 32.00 (20.50, 33.25), respectively. Following the 12-week treatment period, these doses decreased to 19.00 (15.50, 28.50) and 21.00 (18.50, 30.50), respectively. Although the absolute values of insulin doses in the Ins+SZ-A group were greater than those in the Ins+Met group, both during the lead-in period and after 12 weeks of treatment, this difference was not statistically significant. Therefore, we believe that drugs, rather than insulin, decrease hypoglycemia and hyperlipidemia.TIR is a key CGM indicator that describes short-term blood glucose control and quantifies the time within the target range (MBG reflects the average blood glucose level, whereas SDBG reflects the magnitude of overall deviations in glucose levels from the average (LAGE is the difference between the maximum and minimum daily glucose levels, and may be an independent predictor of nocturnal asymptomatic hypoglycemia in patients with T2DM. LAGE measurements of >3.48 mmol/L can be used as an early warning sign of nocturnal asymptomatic hypoglycemia (MODD reflects day-to-day blood glucose excursions, which are the differences between blood glucose values measured at the same time point on two consecutive days. The MODDs of all three groups in our study cohort were lower during the lead-in period than during the screening period. There were no statistically significant differences observed in terms of MODDs among the three groups during the lead-in period or after 12-week treatment period.Postprandial blood glucose control is crucial for achieving overall blood glucose control, with postprandial hyperglycemia being the main factor that leads to general hyperglycemia (After the 12 weeks of treatment, the dinner AUCpp of the Ins+SZ-A group was lower than that of the Ins+Met and Ins groups, indicating that the Ins+SZ-A group experienced a more significant improvement in post-dinner blood glucose levels, which may be partially due to the cumulative effect of α-glucosidase inhibitors (Animal experiments have shown that SZ-A significantly reduces liver weight, liver triglycerides, and total cholesterol levels. However, there is still no data regarding the effects of SZ-A on postprandial blood lipids (Gastrointestinal side effects are one of the limitations to the clinical application of α-glycosidase inhibitors and Met. These may include flatulence, abdominal distension, diarrhea, abdominal pain, and other symptoms. In our experiment, the incidence of GDs in the Ins+SZ-A group was very low. To the best of our knowledge, this is the first research to evaluate the effects of SZ-A or Met combined with premixed insulin on blood glucose fluctuations in patients with T2DM. The combination of SZ-A or Met with premixed insulin not only improved blood glucose control, but also reduced blood glucose fluctuations and blood lipid indicators in our cohort of patients with T2DM whose blood glucose levels could not be controlled through the use of oral medications. SZ-A combined with premixed insulin proved to be better for reducing postprandial blood glucose fluctuations than Met combined with premixed insulin and premixed insulin alone. However, this study also had some limitations worth noting. This was a single-center study with a relatively small number of patients and a study period of only 3 months. Thus, it would be best to extend the treatment period to 6 months or 1 year. Further multi-center studies with larger sample sizes are also warranted to evaluate the safety and efficacy of long-term treatment with SZ-A.The results of this study suggest that the combination of SZ-A and Met with premixed insulin is a potential treatment option for patients with T2DM whose blood glucose levels cannot be adequately controlled by oral medications, and SZ-A combined with premixed insulin may be more suitable for Chinese patients who consume higher levels of carbohydrates. Further prospective studies with more patients over longer periods are required to verify this hypothesis.

PMC10653384

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

PMC10653384

Ethics statement

The studies involving humans were approved by Ethics Review Committee of the First Affiliated Hospital of Harbin Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

PMC10653384

Author contributions

MH, WL, HL

ZM: Writing – original draft. CX: Writing – original draft. HL: Writing – original draft. XG: Writing – original draft. XL: Writing – original draft. WL: Writing – original draft. XM: Writing – original draft. CY: Writing – original draft. MH: Writing – original draft. KZ: Writing – original draft. YH: Writing – original draft. YW: Writing – original draft. HK: Writing – review & editing.

PMC10653384

Acknowledgments

The authors thank the doctors and nurses of the First Affiliated Hospital of Harbin Medical University.

PMC10653384

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

PMC10653384

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

PMC10653384

References

PMC10653384

Purpose

paraplegia, CIVD

VASODILATION, PARAPLEGIA

Communicated by George Havenith.This study examined physiological and perceptual parameters related to cold-induced vasodilation (CIVD) in the fingers and toes of people with paraplegia and compared them with responses observed in able-bodied individuals.

PMC10363085

Methods

paraplegia

COLD, PARAPLEGIA

Seven participants with paraplegia and seven able-bodied individuals participated in a randomized matched-controlled study involving left-hand and -foot immersion in cold water (8 ± 1 °C) for 40 min during exposure to cool (16 ± 1 °C), thermoneutral (23 ± 1 °C), and hot (34 ± 1 °C) ambient conditions.

PMC10363085

Results

paraplegia

PARAPLEGIA

Similar CIVD occurrence was observed in the fingers in the two groups. In toes, three of the seven participants with paraplegia revealed CIVDs: one in cool, two in thermoneutral, and three in hot conditions. No able-bodied participants revealed CIVDs in cool and thermoneutral conditions, while four revealed CIVDs in hot conditions. The toe CIVDs of paraplegic participants were counterintuitive in several respects: they were more frequent in cool and thermoneutral conditions (compared to the able-bodied participants), emerged in these conditions despite lower core and skin temperatures of these participants, and were evident only in cases of thoracic level lesions (instead of lesions at lower spinal levels).

PMC10363085

Conclusion

paraplegia, CIVD

PARAPLEGIA

Our findings demonstrated considerable inter-individual variability in CIVD responses in both the paraplegic and able-bodied groups. While we observed vasodilatory responses in the toes of participants with paraplegia that technically fulfilled the criteria for CIVD, it is unlikely that they reflect the CIVD phenomenon observed in able-bodied individuals. Taken together, our findings favor the contribution of central over peripheral factors in relation to the origin and/or control of CIVD.

PMC10363085

Supplementary Information

The online version contains supplementary material available at 10.1007/s00421-023-05175-7.

PMC10363085

Keywords

Open access funding provided by HEAL-Link Greece.

PMC10363085

Introduction

CIVD, cold injury, paraplegia, heat loss

HEAT, COLD, PARAPLEGIA

Exposure to a cold stimulus causes vasoconstriction of the cutaneous vasculature to reduce heat loss (Tyler et al. It has been proposed that the purpose of the CIVD response may be cryoprotective, that is to minimize the risk of cold injury (Daanen and Ducharme The CIVD response is characterized primarily by the magnitude of the skin temperature (Accordingly, the aim of this study was to examine physiological and perceptual parameters related to CIVD in the fingers and toes of people with paraplegia and compare them with responses observed in able-bodied individuals during exposure to cool, thermoneutral, and hot environments. We reasoned that a predominantly neurally mediated CIVD response would rely on the thermal afferent information emanating from the cutaneous cold sensors and the subsequent centrally mediated thermoeffector drive to the peripheral cutaneous vasculature. A lesion in the spinal cord above the level at which afferent and efferent nerves for a given region enter and exit the spinal cord, respectively, would abolish the neural traffic (Price and Trbovich Accordingly, in this study, we examined physiological and perceptual parameters during cold water immersions in people with paraplegia and able-bodied individuals with the aim to investigate the origin of the CIVD response, namely whether it is central or peripheral. Under the assumption that paraplegic participants have no central control over blood vessels under the level of lesion, the CIVD reactions in paraplegic and able-bodied participants were investigated during exposure to different environmental conditions, resulting in different levels of heat content, since body heat content is known to significantly influence CIVD reactions (Daanen and Ducharme

PMC10363085

Materials and methods

PMC10363085

Experimental protocol

The study included a familiarization session and three experimental sessions. During the familiarization session, participants were informed about all data collection procedures/equipment and underwent anthropometric and body composition (Dual-energy X-ray absorptiometry; (Lunar model DPX Madison, WI).) assessments. Thereafter, participants were requested to undergo three trials, in each being exposed to different environmental conditions inside a 32.5 mFor each session, participants arrived at the same time of the day. They were requested to refrain from caffeine for at least two hours, from food for at least three hours, and from alcohol and exercise for at least 12 h prior to experiment. Upon arrival, participants dressed down to a long-sleeve shirt and a pair of pants 100% cotton (Fig. An able-bodied participant during the data collection. The right sleeve of the shirt was cut at elbow height to avoid constricting blood flow. The blood pressure cuff was comfortably placed at the upper arm without constricting blood flow except when assessing arterial blood pressureThe water tanks used for the warm immersion were 0.58 m

PMC10363085

Measurements

PAD, HEART, COLD

Gastro-intestinal (Physiological and perceptual measurements during the experimental protocolGastro-intestinal temperature (Using surgical tape (3 M Transpore Tape, 3 M Canada), six ceramic chip skin thermistors (MA-100, Thermometrics) were attached on the lower part of the pad on the 2nd finger (i.e., index finger) of both hands and on the lower part of the pad on the 1st, 3rd, and 5th toes of the immersed foot, as well as at on the 1st toe of the non-immersed foot. Data were recorded using a data logger (Smartreader 8 Plus, ACR, Vancouver, Canada).Skin blood flow (SkBF) was monitored with a laser Doppler flowmeter (PF4000 LDPM, Perimed, Stockholm, Sweden, PF5010 LDPM, Perimed, Stockholm, Sweden) at the pad of the 2nd finger in each hand as well as at the distal edge of the 1st toe of each foot. The probe (PR 407 small straight probe, Perimed) on the non-immersed 2nd finger was held in place with a plastic mini holder (diameter: 5 mm; PH 07-5, Perimed), which was fixed to the skin using double-sided adhesive strips (PF 105-3, Perimed) without constricting the finger. All other probes (413 Integrating Probe, Perimed, Stockholm, Sweden) were held in place with a plastic holder (PH 13, Perimed, Stockholm, Sweden). The SkBF data were expressed as absolute values in perfusion units (PU).Sweat rate was measured at the forehead and the belly of the gastrocnemius using the ventilated capsule method (SFM4100, Sensirion, Staefa, Switzerland). Heart rate was monitored using a wireless heart rate system (Polar Team2, Polar Electro Oy, Kempele, Finland). Arterial blood pressure was assessed on the arm of the non-immersed hand (Omron Healthcare, M6 comfort, Kyoto, Japan). Whole body thermal comfort (from 1 = comfortable to 5 = extremely uncomfortable) and thermal sensation (from −3 = cold to + 3 = hot) were recorded using standard scales (Gagge et al.

PMC10363085

Statistical analysis

The 20-s average values for Number of waves (Minimum temperature (Maximum temperature (Onset time (Peak time (Average temperature (Temperature amplitude (ΔA Shapiro–Wilks test was used to test the normality assumption in continuous variables, demonstrating that they were distributed normally. Chi-square tests were used to compare the frequency of CIVDs across the three different environments, the fingers/toes, as well as between the hand and the foot. Since the aim of the study was to identify differences between matched groups the mean data for each phase were used to perform paired sample

PMC10363085

Results

PMC10363085

Frequency of CIVD

C)Colors, CIVD

HEAT, COLD

According to the above definition of CIVD, we observed 75 CIVDs in both groups, distributed as follows: 13 in the cool environment, 17 in the thermoneutral environment, and 45 in the hot environment (Heat map presenting the number of paraplegic and able-bodied participants that demonstrated a CIVD reaction for each minute of the cold immersion during exposure in the cool environment (16 ± 1 °C)Colors indicate frequencies. Gray color indicates lack of CIVD. * = non-immersed foot (all other fingers and toes refer to the immersed limbs)Heat map presenting the number of paraplegic and able-bodied participants that demonstrated a CIVD reaction for each minute of the cold immersion during exposure in the thermoneutral environment (23 ± 1 °C)Colors indicate frequencies. Gray color indicates lack of CIVD. * = non-immersed foot (all other fingers and toes refer to the immersed limbs)Heat map presenting the number of paraplegic and able-bodied participants that demonstrated a CIVD reaction for each minute of the cold immersion during exposure in the hot environment (34 ± 1 °C)Colors indicate frequencies. Gray color indicates lack of CIVD. * = non-immersed foot (all other fingers and toes refer to the immersed limbs)For CIVDs detected in the toes, one participant (level of lesion T4) in the paraplegic group revealed simultaneous and synchronous CIVDs across all toes in the cool environment, two other participants (level of lesion T11 and T12) showed simultaneous and synchronous CIVDs in the thermoneutral environment, and all three participants demonstrated simultaneous and synchronous CIVDs in the hot environment (For the CIVDs detected in the fingers, two participants in the paraplegic group revealed CIVDs in the cool environment, four in the thermoneutral environment, and five in the heat (

PMC10363085

Characteristics of CIVD

SD

SKIN, COLD

The characteristics of CIVD waves across groups and environments are shown in Table S1 as well as in Figs. Skin temperature in the fingers and toes as well as skin blood flow (mean ± SD) in the cool environment (16 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Finger and toe temperatures are indicated with continuous yellow lines in paraplegic participants and with dashed yellow lines in the able-bodied individuals. Finger and toe skin blood flow data are indicated with continuous purple lines in paraplegic participants and with dashed purple lines in able-bodied individualsSkin temperature in the fingers and toes as well as skin blood flow (mean ± SD) in the thermoneutral environment (23 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Finger and toe temperatures are indicated with continuous yellow lines in paraplegic participants and with dashed yellow lines in able-bodied individuals. Finger and toe skin blood flow data are indicated with continuous purple lines in paraplegic participants and with dashed purple lines in able-bodied individualsSkin temperature in the fingers and toes as well as skin blood flow (mean ± SD) in the hot environment (34 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Finger and toe temperatures are indicated with continuous yellow lines in paraplegic participants and with dashed yellow lines in the able-bodied individuals. Finger and toe skin blood flow data are indicated with continuous purple lines in paraplegic participants and with dashed purple lines in able-bodied individuals

PMC10363085

Physiological responses

COLD

The physiological parameters monitored during the protocol are shown in Table S2 as well as Figs. Physiological parameters (mean ± SD) during exposure to the cool environment (16 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Continuous yellow lines indicate results for paraplegic participants and with dashed yellow lines present results for the able-bodied individualsPhysiological parameters (mean ± SD) during exposure to the thermoneutral environment (23 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Continuous yellow lines indicate results for paraplegic participants and with dashed yellow lines present results for the able-bodied individualsPhysiological parameters (mean ± SD) during exposure to the hot environment (34 ± 1 °C) in the two groups. The first 20 min (00:00–00:20) indicate data collected during the baseline phase, the next five min (00:20–00:25) indicate responses during the warm immersion, the next 40 min (00:30–00:70) indicate responses during the cold immersion, and the final five min (00:70–00:75) show responses during the recovery phase. Continuous yellow lines indicate results for paraplegic participants and with dashed yellow lines present results for the able-bodied individualsThe The paraplegic group showed markedly lower leg sweat rate in the hot environment (small to large effect sizes; Table S2, Figs.

PMC10363085

Perceptual data

paraplegia, pain

HEAT, COLD, PARAPLEGIA

Perception of pain and distress in the hand during the cold water immersion were markedly lower for the paraplegic group (small to very large effect sizes; Table S2). Compared to the able-bodied participants, the finger tactile sensitivity of the paraplegic group tended to be higher when assessed using the Semmes–Weinstein monofilaments (small to medium effect sizes) and lower when assessed using the digital esthesiometer (very small to large effect sizes; Table S2). During the cold water immersion and the recovery, the participants with paraplegia reported being more thermally comfortable than the able-bodied individuals in the cool and the thermoneutral environments (very small to medium effect sizes), and this was reversed in the heat (medium effect sizes). Finally, in terms of thermal sensation, the paraplegic group reported feeling colder than the able-bodied group in the cool environment (small to medium effect sizes; Table S2).

PMC10363085

Discussion

paraplegia

COLD, PARAPLEGIA

The principal finding of the present study is the presence of a vasodilatory response in the fingers and toes of participants with paraplegia during immersion of the hands and feet in cold water; a response that is defined as a CIVD in able-bodied individuals. The elevations in the digit skin temperature undoubtedly reflect intermittently restored blood flow, but the nature of these responses—namely the frequency of their occurrence, magnitude, and duration—was different between the two groups. Should the origins of the digit skin temperature fluctuations during cold water immersion not be of the same origin in paraplegics as in able-bodied individuals, then the original premise of our study is compromised. Should the nature of the skin temperature fluctuations be similar, then the data could provide insight regarding the origin of the CIVD response, namely whether it is central or peripheral.

PMC10363085

Effect of paraplegia and ambient temperature on the CIVD response based on finger/toe temperature

paraplegia, CIVD

HEAT, VASODILATION, COLD, PARAPLEGIA

In able-bodied participants, immersion of the hands and feet in cold water during exposure to a hot environment elicited a CIVD response in fingers and toes. The CIVD response in the toes was absent during exposure to thermoneutral and cool ambient conditions. The participants with paraplegia showed a similar reduction of the number of CIVD responses as the ambient temperature decreased from hot to thermoneutral and cool. Yet, contrary to the able-bodied participants who exhibited no CIVD responses in the toes at thermoneutral and cool ambient conditions, CIVD responses were present in the toes of participants with paraplegia.The core body and mean skin temperatures of the participants with paraplegia was lower during the cold water immersions performed in the thermoneutral and cool environments, indicating that they had a lower body heat content during these trials compared to the able-bodied subjects. The above-mentioned observation of more frequent occurrences of toe CIVDs in the participants with paraplegia during the cool and thermoneutral conditions is contrary to what has been observed in able-bodied individuals, namely an attenuation of the CIVD response (Daanen and Ducharme In contrast to the able-bodied participants, who did not exhibit any CIVDs during exposure to thermoneutral and cool ambient conditions, the participants with paraplegia exhibited vasodilation in the toes during these trials. The lack of CIVDs in the toes of able-bodied individuals is not a novel finding (Cheung and Mekjavic Representative data fom one participant with paraplegia (level of lesion: T4) during the warm and cold immesions while being exposed to the thermoneutral environment. In the horizontal axis, light red indicates the warm water immersion and light blue indicates the cold water immersion

PMC10363085

Effect of paraplegia and ambient temperature on skin blood flow and CIVD

cord injury, paraplegia

PARAPLEGIA

The most pertinent issues with regards to the observed indirect evidence (i.e., skin temperature) of the skin blood flow responses in the fingers and toes of participants with paraplegia are: can the responses be defined as CIVDs in the same manner as in the able-bodied population, or are these responses of a different nature and origin, specific to individuals with spinal cord injury at a level that affects the innervation of the toes and not the fingers?Since SkBF fluctuations were observed in some individuals in our paraplegic group and not in others, it is important to consider the potential impact of the level of injury, since the control of SkBF of the lower extremity is mediated from T10 to L2 (Prévinaire et al.

PMC10363085

The possible implication of muscular and vascular atrophy

paraplegia

PARAPLEGIA

Compared to able-bodied individuals, participants with paraplegia demonstrated lower

PMC10363085

The contribution of central and peripheral mechanisms in the etiology of CIVD

paraplegia

COLD, PARAPLEGIA

The present study was designed with the view of contributing to the resolution of the issue regarding the contribution of central and peripheral (local) mechanisms in the initiation of CIVDs during immersion of either the hands or feet in cold water. We considered that our approach of comparing the CIVD response in fingers and toes of able-bodied and paraplegic individuals would provide evidence in support of one or the other. The evidence generated by this study has, perhaps, generated more questions than it has resolved. Indeed, the absence of CIVDs in toes of able-bodied individuals in thermoneutral and cool ambient conditions, but not in the toes of the paraplegics, would favor a local mechanism. As discussed above, the observed skin temperature fluctuations in individuals with paraplegia may have been initiated by nonthermal factors (e.g., bladder stretching), thus confounding our ability to discern the origin of the responses. In this sense, our results favor a central origin of the CIVD response (Flouris and Cheung

PMC10363085

Limitations

paraplegia, CIVD

PARAPLEGIA

We did not monitor bladder stretching or urine production, which could have provided insightful information with regards to the unexplained fluctuations in skin temperature and blood flow of individuals with paraplegia. Also, it is important to note that we did not directly assess sympathetic vasomotor control in the fingers and toes of our participants. Instead, we assumed a lack of sympathetic outflow to the toes of our paraplegic participants and a normal such function in our able-bodied individuals. Future studies should address this gap and should aim to assess CIVD in a larger sample of people with paraplegia. In this regard, it is crucial to ensure that the recruited participants have experienced the spinal cord lesion for > 6 months, as this is known to affect vasomotor and sudomotor function below the level of the lesion. In our study, the time since injury ranged from 2 to 40 years. It would be interesting to explore potential links between the occurrence and characteristics of CIVD and the time since injury, yet our sample size did not allow such analyses. However, we should note that the participants in our paraplegic group that presented these fluctuations were the ones that were injured most recently (i.e., approximately the past two years).It could be argued that the analysis of the area under the curve of the CIVD responses would provide a more integrative result, of more practical relevance than that of a comparison of the individual characteristics of the CIVD response (Wickham et al.

PMC10363085

Practical implications

paraplegia

DER, COLD, PARAPLEGIA

In regions with colder climates, it is often rare for individuals with paraplegia to venture outdoors during periods of extreme cold. Without feedback regarding the thermal status of their feet, they cannot appropriately behaviourally thermoregulate (i.e., adding more insulation, removing themselves from the cold, etc.). The extent to which CIVD responses contribute to the prevention of non-freezing and freezing cold injury in able-bodied individuals remains unresolved (Daanen and van der Struijs

PMC10363085

Conclusions

paraplegia, CIVD

COLD, PARAPLEGIA

In conclusion, our findings demonstrated considerable inter-individual variability in CIVD responses in both the paraplegic and able-bodied groups. We observed vasodilatory responses in the fingers and toes of participants with paraplegia during immersion of the hands and feet in cold water; a response that is defined as a CIVD in able-bodied individuals. While these responses in the toes of the paraplegic participants technically fulfilled the criteria for CIVD, their characteristics are counterintuitive, and it is unlikely that they reflect the phenomenon of CIVD observed in able-bodied individuals. Taken together, the evidence presented herein favor the contribution of central over peripheral factors in relation to the origin and/or control of CIVD. Finally, there are no standardized criteria to identify CIVD for people with paraplegia or able-bodied individuals. The only well-accepted criterion is the continuous increase of at least 1 °C in finger/toe skin temperature. This knowledge gap should be addressed by future studies, potentially adopting the Delphi method, to provide more clarity to the CIVD phenomenon.

PMC10363085

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 303 kb)

PMC10363085

Author contributions

HAD

LT and ADF conceived and designed the research; LT, LGI and ADF performed the experiments; LT and ADF analyzed the data; LT and ADF interpreted the results of experiments; LT prepared the figures; LT, and ADF drafted the manuscript; LT, LGI, BKA, SSC, HAD, IBM, ADF edited and revised the manuscript; LT, LGI, BKA, SSC, HAD, IBM, ADF approved the final version of the manuscript.

PMC10363085

Funding

Open access funding provided by HEAL-Link Greece. This study received no external funding.

PMC10363085

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

PMC10363085

Declarations

PMC10363085

Conflict of interest

The authors declare no conflict of interest.

PMC10363085

Ethical approval

The experimental protocol (ClinicalTrials.gov ID: NCT04215939) conformed to the standards set by the Declaration of Helsinki and was approved by the Bioethics Review Board of the University of Thessaly Department of Physical Education and Sport Science (protocol no.: 1320).

PMC10363085

Informed consent

Informed consent was obtained from all subjects involved in the study.

PMC10363085

Disclaimer

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army, the Department of Defense, or the U.S. Government. Approved for public release; distribution is unlimited. Citations of commercial organizations and trade names in this report do not constitute an official U.S. Department of the Army endorsement or approval of the products or services of these organizations.

PMC10363085

References

PMC10363085

Abstract

PMC10655060

Aims

HF, heart failure, T2DM

HEART FAILURE, RECURRENCE, TYPE 2 DIABETES MELLITUS, ATRIAL FIBRILLATION (AF)

Dapagliflozin has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and heart failure (HF). However, data concerning the association between dapagliflozin and the recurrence of atrial fibrillation (AF), especially in patients following Cox-Maze IV (CMIV), are rare. We aim to explore the effect of dapagliflozin on the recurrence of AF after CMIV with and without T2DM or HF.

PMC10655060

Methods and results

The study of dapagliflozin evaluation in AF patients followed by CMIV (DETAIL-CMIV) is a prospective, double-blind, randomized, placebo-controlled trial. A total of 240 AF patients who have received the CMIV procedure will be randomized into the dapagliflozin group (10 mg/day,

PMC10655060

Conclusion

T2DM

RECURRENCE

DETAIL-CMIV will determine whether the sodium-glucose cotransporter-2 inhibitor dapagliflozin, added to guideline-recommended post-operative AF therapies, safely reduces the recurrence rate of AF in patients with and without T2DM or HF.

PMC10655060

Graphical Abstract

PMC10655060

Introduction

coronary heart disease, arrhythmia, cardiovascular adverse

HEART, CORONARY HEART DISEASE, ATRIAL FIBRILLATION (AF), ARRHYTHMIA

Atrial fibrillation (AF) is the most common arrhythmia. Based on data from the Framingham Heart Study (FHS), the prevalence of AF has increased three-fold over the last 50 years.A new oral hypoglycaemic drug, dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), was confirmed to reduce the risk of cardiovascular adverse events (AEs) and improve coronary heart disease and HF outcomes in multiple clinical trials.

PMC10655060

Objectives

T2DM

RECURRENCE

Accordingly, we are conducting a randomized controlled trial to evaluate whether post-operative oral dapagliflozin can improve AF recurrence after CMIV, regardless of concomitant T2DM or HF.

PMC10655060

Study design

cardiac or cerebrovascular event, AF/AT, atrial flutter

ATRIAL FIBRILLATION, ATRIAL FLUTTER, ATRIAL TACHYCARDIA

This is a prospective, double-blind, randomized, placebo-controlled trial. The manufacturer of dapagliflozin did not provide any financial support or take part in the design of the study. This study is investigator initiated, and the study protocol was in accordance with the Declaration of Helsinki and approved by the ethics committee of Beijing Anzhen Hospital (No. KS2023017). The study was registered at Flowchart of the study. AF, atrial fibrillation; AF/AT, atrial flutter or atrial tachycardia; CMIV, Cox-Maze IV; MACCE, major cardiac or cerebrovascular event.

PMC10655060

Current status of the trial

RECRUITMENT

The study has not yet begun. The start date of recruitment is expected to be 1 September 2023, and the completion of recruitment is expected by late June 2024.

PMC10655060

Patient population

cerebral apoplexy, vascular disease, hyperthyroidism, apoplexy, T2DM

HYPERTHYROIDISM, ACUTE MYOCARDIAL INFARCTION, APOPLEXY, VASCULAR DISEASE

Patients who were hospitalized in Beijing Anzhen Hospital for CMIV of AF were screened for inclusion with written informed consent was obtained from all participants. Patients aged 18 or older with AF undergoing first-time isolated or concomitant CMIV, regardless of concomitant T2DM or HF, were eligible for inclusion. The CMIV procedure was performed in both concomitant with open heart surgery and a stand-alone procedure at our centre. Patients aged 18 or older with AF undergoing first-time stand-alone or concomitant CMIV, regardless of concomitant T2DM or HF, were eligible for inclusion (concomitant CMIV: symptomatic AF patients undergoing other cardiac surgical procedure; stand-alone CMIV: symptomatic AF patients who have failed medical management and prefer a surgical approach, have recurrent AF after CA or are not candidates for CA). Exclusion criteria were dapagliflozin allergy; hyperthyroidism; acute myocardial infarction, cerebral apoplexy, and other vascular disease during the past 6 months; following heart surgery within the last 3 months; estimated glomerular filtration rate (eGFR) < 45 mL/min; history of oral SGLT2i; estimated survival period < 12 months; pregnant and lactating women; left atrial diameter > 65 mm; and refusing to sign informed consent. Additional inclusion and exclusion criteria are listed in Main inclusion and exclusion criteria of the DETAIL-CMIV trialAge ≥ 18 yearsPatients who need first-time stand-alone or concomitant Cox-Maze IV procedure (concomitant CMIV: symptomatic AF patients undergoing other cardiac surgical procedure; stand-alone CMIV: symptomatic AF patients who have failed medical management and prefer a surgical approach, have recurrent AF after catheter ablation or are not candidates for catheter ablation)Patients who have the ability and willingness to abide by all the subsequent review and requirementsDapagliflozin allergyHyperthyroidismAcute myocardial infarctionCerebral apoplexy and other vascular disease during the past 6 monthsFollowing heart surgery within the last 3 monthseGFR < 45 mL/minHistory of oral sodium-glucose cotransporter-2 inhibitorsEstimated survival period < 12 monthsPregnant and lactating womenLeft atrial diameter > 65 mmRefusing to sign informed consent

PMC10655060

Randomization and blinding

SEPARATION

The random allocation sequence was generated with computer-generated random numbers by the study statistician, and sequentially numbered opaque envelopes containing the treatment allocation were utilized to conceal the sequence. Participants will be randomly assigned 1:1 to dapagliflozin (10 mg once a day) or matched placebo with blocked randomization of 10 patients in each block to ensure balance in the treatment groups in case the study needs to be stopped early. Patients and all study personnel (except the independent study statistician) will be kept blinded to the treatment allocation. The trial will adhere to established procedures to maintain separation between the staff that performs the outcome measurements and the staff that delivers the intervention. Staff members who obtain the outcome measurements will not be informed of the treatment group assignment. The intervention staff members who deliver the intervention will not perform the outcome measurements. The dapagliflozin and placebo are packaged in an identical manner with the same labelling, tablet appearance and schedule.

PMC10655060

Surgical procedure

RA, bipolar, transmurality

WEST, ARRESTED

All the CMIV procedures were performed under cardiopulmonary bypass (CPB) with median sternotomy. To reduce the variation among surgeons, we require the CMIV to be performed by qualified surgeons. After the initiation of normothermic CPB, both sets of pulmonary veins are then bluntly dissected, mobilized, and encircled with a urine catheter. Lesions from right atrial (RA) lesion set are performed on the beating heart and with temperature cooled to 34°C. Then, a small purse-string suture is placed at the base of the RA appendage that is wide enough to accommodate one jaw of the bipolar radio frequency (RF) ablation clamp. An ablation lesion is created along the free wall of the right atrium through the purse string down the aortic side of the RA appendage. A vertical right atriotomy is made extending from the intra-atrial septum up towards the atrioventricular groove near the free margin of the heart (at least 2 cm from the free wall ablation). From the inferior aspect of the incision, the RF ablation clamp is used to create ablation lines up to the superior vena cava and down towards the inferior vena cava. A linear cryoprobe is used to create an endocardial ablation line from the superior aspect of this atriotomy down onto the tricuspid annulus at the 2 o’clock position. All cryoablations are performed for 3 min at a temperature below −60°C. The linear cryoprobe is then inserted through the previously placed purse-string suture, and an endocardial ablation line is created down to the tricuspid annulus at the 10 o’clock position. Next, the left atrial lesion set is performed on the arrested heart after aortic cross-clamping. The heart is retracted, and the left atrial appendage (LAA) is exposed and amputated. Through the amputated appendage, the bipolar RF clamp is used to create a connecting lesion into the left inferior pulmonary vein. The LAA is then oversewn in two layers with a running polypropylene suture. The coronary sinus is marked with methylene blue between the right and the left coronary circulations. A standard left atriotomy is then performed, and the bipolar clamp is used to create ‘roof’ and ‘floor’ lesions from the superior and inferior aspects of the atriotomy to the left superior and inferior pulmonary veins, respectively. The RF ablation clamp is also used to create an ablation from the inferior margin of the atriotomy towards the mitral annulus and across the coronary sinus. As the RF bipolar clamp cannot reach the annulus itself, a bell-shaped cryoprobe is used to make an endocardial lesion to the mitral annulus at the end of the mitral isthmus lesion. To complete the left atrial isthmus ablation, an epicardial cryoablation is performed over the coronary sinus in line with the endocardial lesion. The energy source used for each procedure was AtriCure Inc., West Chester, OH, USA. It was repeated three to four times for every ablation to ensure the transmurality. Concomitant cardiac surgery was performed after ablation; for patients with severe coronary artery disease, coronary artery graft bypass was a priority to ensure sufficient cardioplegic solution perfusion.

PMC10655060

Study intervention and background medication

Following CMIV, patients will be randomly assigned to oral dapagliflozin therapy or matched placebo in blocks of ten. Dapagliflozin will be initiated on the first morning after CMIV at a dose of 10 mg once daily until 3 months post-operation. The start date of the observation will be set as the first intervention date. Patients in both groups will undergo 24-h post-operative rhythm monitoring and will be treated with continuous intravenous amiodarone as the standard of care.All patients will be treated with amiodarone post-operatively, and this trial will test dapagliflozin added to the background medication after CMIV. Routine oral amiodarone at 200 mg twice a day will be administered for 3 months when the patients leave the intensive care unit. Low molecular weight heparin combined with warfarin will be used during the early post-operative period and then treated with warfarin alone after the international normalized ratio (INR) reaches the ideal value (INR of 2.0–3.0).

PMC10655060

Outcome measurement

malignant arrhythmias, AF/AT, cardiovascular death, atrial tachycardia, atrial tachyarrhythmia, stroke, MACCEs, atrial flutter

STROKE, EVENTS, ATRIAL FLUTTER, ATRIAL TACHYCARDIA

Primary endpoint is any documented atrial tachyarrhythmia [AF, atrial flutter or atrial tachycardia (AF/AT)] lasting 30 s following a blanking period of 3 months after CMIV.Secondary endpoints are as follows: (i) any documented atrial tachyarrhythmia [AF, (AF/AT)] at the 6-month follow-up monitoring session after CMIV; (ii) any documented atrial tachyarrhythmia [AF, (AF/AT)] at the 12-month follow-up monitoring after CMIV; and (iii) major adverse cardiac or cerebrovascular events (MACCEs, including cardiovascular death, malignant arrhythmias, and stroke) at 6 or 12 months after CMIV.

PMC10655060

Data collection

arrhythmia, arrhythmia-related

EVENTS, EVENT, ARRHYTHMIA, COMPLICATIONS

Study visits are scheduled to occur before randomization and at 3, 6, and 12 months; a detailed medical history, a routine blood pressure measurement and physical examination, laboratory testing, and 48- to 72-h Holter monitoring will be conducted at each visit. All patients with arrhythmia-related symptoms, especially after the blanking period, will be encouraged to undergo electrocardiography (ECG) during their symptomatic periods, and such events will be registered with the study investigator. In addition, patients who experience longer-lasting arrhythmia symptoms will be instructed to contact local hospitals and undergo cardioversion within 48 h, and additional monitoring (e.g. extra Holter or event monitoring) will be performed for patients with arrhythmia symptoms who cannot be monitored during an acute episode. All ECGs and Holter monitoring will be reviewed by a blinded study investigator. Peri-operative clinical and baseline data, such as the type of AF, medical history, laboratory results, complications, cardiac ultrasound features, general information about the operation, a record of surgical ablation, post-operative complications, and pre-operative medication, will be collected through the electronic medical record database.

PMC10655060

Adverse events monitoring and interim analysis

DIABETIC KETOACIDOSIS, ADVERSE EVENT, EVENTS, HYPOGLYCAEMIA

Adverse events will be constantly monitored by investigators during the process of the study through regular medical check-ups, and the details will be immediately reported to the principal investigator once an AE occurs, regardless of the causal relationship with dapagliflozin. Only serious AEs and AEs of interest or those leading to premature study drug discontinuation, study drug interruption, or dose reduction are recorded. Adverse events of interest include volume depletion, renal events, major hypoglycaemia, and potential diabetic ketoacidosis.The collection of cardiovascular events and other serious AEs will be performed by two well-trained staff members, and they will follow up specifically for these events by telephone every month for every participant with a phone number who has given prior consent during enrolment. In addition, participants will also be taught and asked to report whether they have experienced any cardiovascular events or other serious AEs. All captive cardiovascular events and other serious AEs will be adjudicated and graded by two well-trained staff members in order to reach a consensus.Once 75% of the primary events are confirmed, an interim analysis will be performed by using a Haybittle–Peto rule, and if the superiority of dapagliflozin over placebo is demonstrated for the primary outcome with a sided level of 0.001, early termination of the trial can be recommended. The significance level of the final analysis will be determined by the Haybittle–Peto rule, depending on the actual number of events and the timing of the interim analysis.

PMC10655060

Sample size estimation

RECURRENCE

According to our published work, the recurrence rate of AF after CMIV is 37.9% in patients without oral dapagliflozin therapy.

PMC10655060

Statistical analysis

REGRESSION, EVENT, RECURRENCE

Analyses will be performed according to the intention-to-treat principle. Patients who are lost or die before completing the 3-month follow-up visit will be excluded from the analysis of the primary endpoint. The proportions of patients with recurrence at follow-up in the dapagliflozin group and the placebo group will be compared using the chi-square test. In general, the last date of contact for each patient will be considered the censoring date for those without any primary outcome event. The cumulative incidence of the first occurrence of any event in the primary endpoint will be plotted by the Kaplan–Meier curve. In addition, the logistic regression model will be used to assess possible predictors for recurrence at follow-up, and pre-specified relevant clinical characteristics will be tested first in a univariate and then in a multivariate-adjusted model.Continuous variables will be expressed as the mean ± standard deviation or the median and the interquartile range, and Student’s

PMC10655060

Discussion

T2DM

RECURRENCE, EVENTS, TUMOUR NECROSIS, INFILTRATION

Dapagliflozin has emerged as a powerful agent to reduce the incidence of cardiovascular events in patients with T2DM and HF. Although the mechanisms of dapagliflozin with cardiovascular events have not been fully demonstrated, studies have shown that dapagliflozin can reduce the production of the inflammatory cytokines interleukin-6 and tumour necrosis factor-α and limit macrophage infiltration in a normoglycaemic rabbit model, which exerts its anti-inflammatory effect.The relationship between the incidence of new-onset AF and SGLT2i treatment has been previously reported. Early retrospective studies showed that there was no significant difference between SGLT2i treatment and other hypoglycaemic agents,In conclusion, the DETAIL-CMIV study is the first dedicated clinical trial to demonstrate the preventive effects of dapagliflozin on the recurrence of AF in patients who need CMIV procedures with and without T2DM or HF. The results of this study may have a large impact on the treatment application of dapagliflozin.

PMC10655060

Authors’ contributions

Z.P., Y.X.Y., F.O., K.H., and X.B.Y. conducted the study, reviewed the manuscript, and contributed to the discussion. Z.P. wrote and edited the manuscript. Z.P., Y.X.Y., F.O., K.H., and X.B.Y. made substantial contributions to the conception and design and acquisition of data, drafted the article or revised it critically for important intellectual content, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.

PMC10655060

Funding

None declared

PMC10655060

Data availability

All relevant data are within the manuscript and its Supporting Information files.

PMC10655060

Clinical trial registration number

NCT05816733.

PMC10655060

Ethics approval

The study protocol was in accord with the Declaration of Helsinki and approved by the ethics committee of Beijing Anzhen Hospital (No. KS2023017).

PMC10655060

References

PMC10655060

Introduction

Assessment in the educational field commonly uses Multiple Choice Questions (MCQs), because this question type offers high reliability and easy machine-marking. However, it also allows for cueing (i.e., answering questions based on cues in the question or answer options rather than on content knowledge) and stimulates a recognition-based study approach [Although other question formats have been proposed to circumvent the limitations of MCQs, such as uncued questions and extended matching questions [Although the use of VSAQs in medical assessments is increasing, evidence regarding validity and reliability of this question type in the medical setting is mainly based on studies from a single research group, consisting of teachers experienced in developing and marking VSAQs [However, it remains unclear whether the application of VSAQs by teachers with less experience in writing and marking VSAQs, in a different population, country, and medical educational setting yields the same results. Before VSAQs can be implemented in a wider context, more evidence is needed. Therefore, we aimed to externally validate the positive results of VSAQs regarding reliability, discrimination, and acceptability in a cohort of Dutch medical undergraduate students with non-expert teachers. Additionally, we wanted to explore the impact of VSAQs on cueing effects and student experiences of VSAQ-assessment. In order to achieve these aims, we partially replicated the study design of Sam

PMC10348524

Methods

PMC10348524

Setting

AEES

This study was simultaneously performed in two different student cohorts (cohort 2019 and cohort 2020) using the same study design. First year students (cohort 2020) followed the fundamental course “(A) Set-up of both courses (RM and DA) with the formative exam and contents, summative exam and contents, and the Automated Education Evaluation System (AEES) (B) Flowchart of the study participants.

PMC10348524

Formative exam

To determine reliability, discrimination, cueing effects, and students’ insights in the formative exams of the RM and DA courses, students were randomly assigned to a group starting with MCQs (RM-MCQAfter having finished the first part of the formative exam (either MCQs or VSAQs) students were asked to rate three statements on a 5-point Likert scale (strongly disagree, disagree, neutral, agree, strongly agree) and one question ranging from 1 to 10, based on the specific question format with which they were just tested: 1) We determined reliability and discriminative capability for content knowledge. The average score, calculated over MCQs and VSAQs separately, was stratified by whether students took MCQs or VSAQs first. Cueing was measured by comparing the answer to an MCQ with the answer to the corresponding VSAQ. We looked at cueing per question (i.e., how often did cueing occur per individual question) and cueing per person (i.e., in how many questions did cueing occur per individual student). We discerned positive and negative cueing. In positive cueing, students used clues in either the MCQ question and/or answer options to arrive at the right answer, which was not possible in VSAQs because no answer options were available. In our study, this could be observed when a student answered a VSAQ incorrectly, but the equivalent MCQ correctly. Negative cueing happens when students are misled by an incorrect answer option in a MCQ (e.g., due to a distractor that is too plausible). In our study, this was derived from a student being able to answer the VSAQ correctly, but not able to give the correct answer to the equivalent MCQ. Although it might have been of influence, the probability of guessing the right answer could not be taken into account. Students’ insights were determined from the evaluation questions asked midway through and at the end of the formative exam.

PMC10348524

Summative exam

AEES

The summative exams of RM and DA were rewritten to replace part of the MCQs with VSAQs (45 in RM and 16 in DA). For RM, this was done through rewriting existing MCQs, whereas for DA, a 2-hour workshop was organized for teachers on how to write VSAQs. Question writers in both courses received written instructions about how to write VSAQs based on information provided by the author of the initial paper on VSAQs, as can currently be found in the publication by Bala VSAQ review time per question for each teacher was recorded in DA to determine acceptability. The total reviewing time per question was recorded by the reviewer using the timer function on a smartphone. Reviewing time started when the reviewer first looked at the question and ended when the question was fully resolved. This included both reviewing the answers and discussion with other teachers when necessary. Because the marking of only a few VSAQs of the exam was recorded during the initial data collection, which impeded a correct and unselected overview of the reviewing time, one year later the reviewing time of all VSAQs in that year’s summative exam was collected again. The AEES questionnaire was supplemented with two questions regarding students’ insights: 1)

PMC10348524

Statistical analysis

Continuous variables are presented as mean (standard deviation) or median (interquartile range) depending on their distribution. Categorical variables are presented as number (proportion). Reliability was determined by calculating the Cronbach’s α or the VSAQs and MCQs in both formative exam formats, which is a measure of internal correlation between items on a test level [

PMC10348524

Ethical approval

This study was reviewed and approved by the Educational Research Review Board of the Leiden University Medical Center (file number: OEC/ERRB/20201208/1).

PMC10348524

Results

Of the 335 students who took the formative exam in RM, 216 students were included in our study. In DA, 159 of the 259 students who took the formative exam were included (

PMC10348524

Reliability and discrimination

We compared the VSAQs of students starting with VSAQs with the MCQs of students starting with MCQs. This comparison reflects the results of the VSAQs and MCQs that are not influenced by prior questions. VSAQs had higher reliability compared to MCQs (Cronbach’s α 0.74 vs. 0.57 in RM; 0.87 vs. 0.83 in DA for VSAQs vs. MCQs, respectively) (

PMC10348524

Cronbach’s alpha, average R

MCQ, multiple choice question; VSAQ, very short answer question; SD, standard deviation.

PMC10348524

Acceptability

In the initially collected data, the average reviewing time per VSAQ by one teacher in the summative exam of DA (7 VSAQs, 308 students) was 2 minutes and 20 seconds (SD 52 seconds). Additionally, on average 2 minutes and 9 seconds (SD 2 minutes and 36 seconds) were spent replying to comments and consultation of other teachers. The maximum time spent on a single VSAQ was 11 minutes and 24 seconds. One year later (22 VSAQs, 338 students), the average time spent on reviewing questions in DA was 1 minute and 58 seconds (SD 40 seconds) and consultation of other teachers took on average 36 seconds (SD 47 seconds).

PMC10348524

Secondary outcomes

POSITIVE

Positive cueing, defined as a correctly answered MCQ with an incorrectly answered equivalent VSAQ, occurred on average more often per student in RM-VSAQ

PMC10348524

Positive and negative cueing per person in MCQ

MCQ, multiple choice question; VSAQ, very short answer question; IQR, interquartile range.

PMC10348524

Positive and negative cueing per question in MCQ

MCQ, multiple choice question; VSAQ, very short answer question; IQR, interquartile range.When asked whether they found the questions easy, students who had been answering only VSAQs more often disagreed compared to students who had been answering MCQs only in the DA course (EQ2: 3, IQR 2–3 vs. 2, IQR 2–2), but students estimated their final grade to be higher if they had started with VSAQs (

PMC10348524

Students’ experiences and grade estimates of the MCQs and VSAQs in the formative exam.

Distribution of the answers given to the 5-point Likert scale evaluation questions halfway through the exam after the MCQs or VSAQs and at the end of the exam; and estimates of their grade halfway through the exam in RM (A, B, C) and DA (D, E, F).

PMC10348524

Discussion

POSITIVE

In this study we aimed to externally validate the earlier results regarding reliability, discrimination, and acceptability of VSAQs compared to MCQs in a cohort of Dutch medical undergraduate students, based on earlier work by Sam The higher reliability and discrimination but lower test scores of VSAQs compared to MCQs may in part reflect the decreased possibility of guessing correctly in VSAQs, and are line with Sam The teachers who graded the VSAQs deemed the reviewing time of VSAQs acceptable. This is supported by previous studies that found comparable and shorter review times, using different marking systems, multiple examiners, and more questions [Positive cueing per student occurred more often in the students who started with VSAQs, which is in line with the findings of Sam Looking at students’ experiences, we found results comparable with Sam Study strengths are the randomized design, studying two different courses, and the investigation of student perspectives. Furthermore, the fact that teachers who participated in our study had limited experience with VSAQs allowed us to validate the previous results in an independent setting with less experienced teachers. Limitations are the seemingly poor question quality in the formative RM exam, and the relatively small sample size. Furthermore, due to the low-stakes nature of the formative exam, we cannot be certain that students performed at their best when answering the questions. To determine acceptability, we used only one reviewer who logged the times by hand, leading to less accurate reviewing times. To obtain a more precise measure of acceptability, these findings could be extended by using multiple examiners, more VSAQs and automatically logged times.Although we validated the VSAQs and investigated student experiences in a medical cohort, we believe that the strengths of VSAQs compared to MCQs are generalizable to other educational fields. Especially, student experiences were mainly related to VSAQs without a focus on a medical context. Real life situations rarely offer a clear single best answer or a list of possible answers. Moreover, in any field open essay questions or other higher-order questions are costly to implement. Although further studies should extend these results to general higher education, our results show VSAQs may provide a promising alternative to MCQ-based assessment in education in general.In conclusion, this study confirms the positive results of Sam

PMC10348524

Supporting information

PMC10348524

Median (IQR) scores of the 5-point Likert scale evaluation questions (EQ1-3 and EQ5-9) and estimated grade question (EQ4) in the formative exam.

EQ1-4 halfway of the exam after the MCQs (MCQ(DOCX)Click here for additional data file.

PMC10348524

Distribution of the answers given to the 5-point Likert scale evaluation questions halfway of the formative exam after MCQs (MCQ

(DOCX)Click here for additional data file.

PMC10348524

Distribution of the answers given to the 5-point Likert scale evaluation questions at the end of the formative exam.

(DOCX)Click here for additional data file.

PMC10348524

Median (IQR) scores and distribution of the answers given to the 5-point Likert scale evaluation questions after the summative exam.

(DOCX)Click here for additional data file.

PMC10348524

Median (IQR) scores of the 5-point Likert scale questions on constructive alignment after the summative exam (1: strongly disagree, 2: disagree, 3: neutral, 4: agree, 5: strongly agree).

(DOCX)Click here for additional data file.The authors wish to thank all members of the research group of the Centre for Innovation in Medical Education at Leiden University Medical Centre for their critical appraisal of the research protocol and all the students for their willingness to participate and valuable feedback.

PMC10348524

References

PMC10348524

Purpose

MBC

METASTATIC BREAST CANCER

A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC.

PMC9823079

Methods

BRAIN METASTASES, DISEASE

In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety.

PMC9823079