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Background:Response surface pathway (RSP) design has been recently developed and described for dose-finding studies. The aim of this paper was to introduce and demonstrate additional procedures to strengthen and generalize the design and combine RSP with classical study design. Materials and methods: Nine bull calves and six heifer calves were included in an unbalanced 2 × 2 Latin Square (LSQ) designed study with large and small aperture bottle teats. The two LSQ sequences were performed with independent randomized three-level between-patient RSP design with an odd number of response classifications. The milk temperature window was 8°C-38°C with a mid temperature of 23°C. X-rays of the abdominal cavity were taken before, during, and immediately after intake of milk and recorded as "milk", "trace", or "no milk". Based on the results of the first design level, the milk temperatures for five calves in the second design level were obtained by a randomization procedure. A similar procedure was performed for seven calves in the third design level. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Results: Starting with a low number of subjects and increasing this number with increasing design levels reduces the sample size without reducing the power. The suggested randomization procedure worked as expected. No milk in Rumen was recorded and minimum milk temperature (MMT) was estimated to be ≤8°C for both teats. The odd number of response categories increases the flexibility of RSP, enabling category redefinition in hindsight from "trace" to "uncertain". After category redefinition, MMT for large bottle teat was estimated to be 14.3°C (95% confidence interval: 8.3-20.3°C), but 8°C for small. Conclusion:The suggested changes and additional procedures increase the strength and flexibility of the RSP design. Keywords: k-adjustment factor, Latin Square design, patient reduction in clinical trials, randomized response surface pathway design BackgroundDuring the first few weeks of life, milk is the primary source of nutrition for the dairy calf. Over the milk feeding period, the calf has an anatomical feature called the esophageal groove or sulcus reticuli. The groove, when activated, turns into a tube allowing the milk to pass by the reticulorumen straight into the abomasum where the milk is digested.1 Activation of the reticular groove is caused by many factors, including the smell and taste of milk, milk temperature, sucking behavior, and body posture while drinking.2 If the esophageal groove is not properly closed, milk can enter Rumen, the

<p class="abstract"><strong>Background:</strong> Cheese is a major source of long-chained vitamin K2 variants. How intake of vitamin K2 rich cheese affects vitamin K and osteocalcin has not been studied. The aim was to establish a maximum efficacy dose (MED) after daily intake of vitamin K2-rich cheese (Jarlsberg^®) based on increase in ratio between carboxylated and undercarboxylated osteocalcin during a five-week diet.</p><p class="abstract"><strong>Methods:</strong> 20 healthy healthy volunteers (HV) were recruited. The daily intake of Jarlsberg^® cheese in the study varied from 20 to 152 g. Clinical investigation was performed initially and after three, four and five weeks with measurement of vital signs, hematological and biochemical variables, carboxylated and undercarboxylated osteocalcin and vitamin K. The ratio OR= carboxylated/undercarboxylated osteocalcin was the main variable.</p><p class="abstract"><strong>Results:</strong> The MED decreased with treatment duration and was estimated to 57 g/day (95% CI: 47-67) after five weeks diet, resulting in a mean OR increase of 30% (95% CI: 23.8-36.8). Both OR and serum osteocalcin followed a quadratic dose response curve. For osteocalcin, a maximal increase of 46% was estimated at 59 g/day for five weeks. The serum content of long-chained vitamin K2 increased significantly with increasing cheese dose. The increase were mainly obtained the first three weeks and kept unchanged the following two weeks. The cheese doses close to the MED caused nearly significant reductions in total cholesterol, LDL-cholesterol, the LDL/HDL ratio and significant reduction in the blood pressures after five weeks diet (p≤0.05).</p><p class="abstract"><strong>Conclusions: </strong>MED of Jarlsberg® cheese was estimated to 57 g/day. Daily intake of Jarlsberg^® cheese increased the osteocalcin level, vitamin K2 and positively affected the lipid patterns and blood pressure.</p>

Background:The response surface pathway (RSP) design obtains a random walk pathway, does not need an assumed statistical model, reduces the sample size without reducing accuracy, and covers predefined dose windows. RSP includes one interventional and one result variable without random allocation of doses between design levels. This study aims to present RSP with two interventional and one result variables, combining between-and within-patient models and introduce a randomization procedure in a clinical situation. Methods: To estimate optimal efficacy dose and spreading duration of particulate CaO powder, material consisting of 18 net pens with salmon indicated for lice treatment was required. The study was performed as a randomized "between-patient" RSP designed trial with CaO dose as the interventional variable and percentage lice reduction as the outcome. Each net pen received three treatments with 24-hour intervals of unchanged CaO dose and a starting spreading duration of 2 hours. The change in spreading duration followed a "within-patient" RSP procedure with percentage lice reduction as the outcome. In all participating fish farms, one net pen remained untreated and was used as control. Results: The minimum and the optimal efficacy doses were estimated to be 6.1 g/kg and 8.5 g/kg biomass (bm), respectively. In order to optimize lice reduction, the spreading duration increases with increasing CaO dose. The minimum efficacy combination was predicted to be 6.1 g/kg bm administered in 2:00 (h:mm) and the optimal to be 8.5 g/kg bm in 3:00. Three of the seven net pens allocated to 7.4 g/kg bm erroneously received 8.5 g/kg and due to weather circumstances three other net pens became untreated. Consequently, accuracy of the predictions was slightly reduced. Conclusion: The two-dimensional RSP design combining between-and within-patient RSP detected its power and predicted the two interventional variables to obtain minimum and optimal efficacy with sufficient accuracy.

<p class="abstract"><strong>Background:</strong> Daily maximum effective dose (MED) of Jarlsberg® increased the serum osteocalcin (tOC) level, vitamin K2 and affected the lipid pattern positively. The aim of the study was to estimate and verify a daily maintenance dose.</p><p class="abstract"><strong>Methods:</strong> 12 healthy female volunteers (HV) were included in a de-escalation study after a six week run-in period on the daily MED of 57 g Jarlsberg® cheese. A 3-level within-patient response surface pathway (RSP) design with individual starting values was developed. Another 12 HVs were included in a new study with a six week run-in period on MED followed with six weeks on the estimated maintenance dose. All HVs were premenopausal female between 20 and 52 years of age. The main variable in the studies was the tOC level.</p><p class="abstract"><strong>Results:</strong> tOC, cOC and the vitamin K2 variants increases significantly (p&lt;0.01) during the run-in period on daily MED of Jarlsberg® in both studies. The maintenance daily dose was estimated to 45 g (95% CI: 38-52 g/day) and used in the new study. The tOC level was reduced from 19.8 ng/ml (95% CI: 12.0-27.6) obtained in the run-in period to 18.5 ng/ml (95% CI: 11.7-25.3) during the maintenance part. This represents a reduction of 6.6%. The sum of vitamin K2 variants changed from 0.58 ng/ml on MED of Jarlsberg® to 0.59 ng/ml (95% CI: 0.37-0.82) during the maintenance period.</p><p class="abstract"><strong>Conclusions: </strong>Daily MED of Jarlsberg® cheese increases tOC, cOC and the vitamin K2 level. The maintenance Jarlsberg® dose was estimated to 45 g/day and verified as sufficient.</p>

At birth, calves are functionally monogastric and remain so for the first weeks of life. Milk in the rumen may cause indigestion, diarrhea, and reduced growth. Calves are often fed cold milk from a large-aperture teat, but warm milk and sucking behavior are believed to trigger the esophageal reflex. The aim of this study was to use radiography to estimate the lowest milk temperature that can be given to dairy calves at high and low intake rates without causing milk in the rumen. Our hypothesis was that cold milk drunk at high speed would cause insufficient closure of the esophageal groove and hence milk in the rumen. Fifteen Norwegian Red calves, 9 to 27 d of age, weighing between 45.5 and 71.0 kg, were tested according to the response surface pathway design. Each calf was offered 4 L of milk from both a small-(2 mm) and a large-aperture (19 mm) teat. The milk contained barium sulfate, and radiography was applied before, during, and after the milk meal. Following radiography, the calves were returned to a group pen and observed for 2 h using continuous live behavioral observation to detect signs of abdominal pain or discomfort. Starting with a low number of subjects and increasing this number with increasing design levels reduces the sample size without reducing the statistical power. The minimum milk temperature was estimated to be 8°C. No behavioral signs of pain or discomfort were observed, but shivering was noted in several calves drinking 8°C milk. These results strengthen the argument that calves can be fed large milk meals without risk of causing milk in the rumen, even cold milk drunk at high speed.

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<p class="abstract"><strong>Background:</strong> The aim of this paper is to introduce and evaluate the RSP design with two interventional and one response variable exemplified by estimating minimum efficacy dose (MED) of osteopathic manual therapy (OMT) in treatment of gastroesophageal reflux disease (GERD).</p><p class="abstract"><strong>Methods:</strong> 15 GERD patients, divided in three design-level with three, five and seven patients. The study was performed as a randomized two-dimensional, between-patient RSP designed multicenter study with two interventional– and one response variable. The interventional variables “Number of OMT’s” and “Treatment Interval” with common response variable, formed two independent one-dimensional randomized between-patient RSP studies. The response variable was percent reduction in sum of the five GERD score from baseline. Three GERD patients were allocated on the first design level and given six OMT with five days’ interval. Based on results obtained in the first and second design level, five patients were included to the second design level and seven to the third.</p><p class="abstract"><strong>Results:</strong> The two-dimensional randomized between-patient RSP-design with the combined outcome procedure worked as expected. The percent reduction in GERD score increased with increasing number of OMT’s and time intervals. This increase leveled out after three to five OMT’s and three to four days between treatments. A clinical interaction between the two interventional variables was obtained. The estimated MED of OMT in treatment of GERD was three treatments with two days between treatments.</p><p class="abstract"><strong>Conclusions: </strong>The suggested two-dimensional, randomized between-patient RSP-design worked as expected and estimated MED of OMT in GERD patient sufficiently.</p><em> </em>